Many members of the HDAC family require zinc (Zn) to function properly. For instance, the isozyme histone deacetylase 6 (HDAC6) is a zinc-dependent histone deacetylase that possesses histone deacetylase activity. Other family members include HDACs 1-5 and 7-11. (De Ruijter et al., Biochem. J. 2003. 370; 737-749).
HDAC6 is known to deacetylate and associate with α-tubulin, cortactin, heat shock protein 90, β-catenin, glucose-regulated protein 78 kDa, myosin heavy chain 9, heat shock cognate protein 70, and dnaJ homolog subfamily A member 1 (reviewed in Li et al., FEBS J. 2013, 280: 775-93; Zhang et al., Protein Cell. 2015, 6(1): 42-54). Diseases in which HDAC6 inhibition could have a potential benefit include cancer (reviewed in Aldana-Masangkay et al., J. Biomed. Biotechnol. 2011, 875824), specifically: multiple myeloma (Hideshima et al., Proc. Natl. Acad. Sci. USA 2005, 102(24):8567-8572); lung cancer (Kamemura et al., Biochem. Biophys. Res. Commun. 2008, 374(1); 84-89); ovarian cancer (Bazzaro et al., Clin. Cancer Res. 2008, 14(22):7340-7347); breast cancer (Lee et al., Cancer Res. 2008, 68(18):7561-7569; Park et al., Oncol. Rep. 2011, 25: 1677-81; Rey et al., Eur. J. Cell Biol. 2011, 90: 128-35); prostate cancer (Seidel et al., Biochem. Pharmacol. 2015 (15)00714-5); pancreatic cancer (Nawrocki et al., Cancer Res. 2006, 66(7):3773-3781); renal cancer (Cha et al., Clin. Cancer Res. 2009, 15(3): 840-850); hepatocellular cancer (Ding et al., FEBS Lett. 2013, 587:880-6; Kanno et al., Oncol. Rep. 2012, 28: 867-73); lymphomas (Ding et al., Cancer Cell Int. 2014, 14:139; Amengual et al., Clin Cancer Res. 2015, 21(20):4663-75); and leukemias such as acute myeloid leukemia (AML) (Fiskus et al., Blood 2008, 112(7); 2896-2905) and acute lymphoblastic leukemia (ALL) (Rodriguez-Gonzalez et al., Blood 2008, 1 12(11): Abstract 1923)).
Inhibition of HDAC6 may also have a role in cardiovascular disease, including pressure overload, chronic ischemia, and infarction-reperfusion injury (Tannous et al., Circulation 2008, 1 17(24):3070-3078); bacterial infection, including those caused by uropathogenic Escherichia coli (Dhakal and Mulve, J. Biol. Chem. 2008, 284(1):446-454); neurological diseases caused by accumulation of intracellular protein aggregates such as Alzheimer's, Parkinson's and Huntington's disease (reviewed in Simoes-Pires et al., Mol. Neurodegener. 2013, 8: 7) or central nervous system trauma caused by tissue injury, oxidative-stress induced neuronal or axomal degeneration (Rivieccio et al., Proc. Natl. Acad. Sci. USA 2009, 106(46):19599-195604); and inflammation and autoimmune diseases through enhanced T cell-mediated immune tolerance at least in part through effects on regulatory T cells, including rheumatoid arthritis, psoriasis, spondylitis arthritis, psoriatic arthritis, multiple sclerosis, lupus, colitis and graft versus host disease (reviewed in Wang et al., Nat. Rev. Drug Disc. 2009 8(12):969-981; Vishwakarma et al., Int. Immunopharmacol. 2013, 16:72-8; Kalin et al., J. Med. Chem. 2012, 55:639-51); and fibrotic disease, including kidney fibrosis (Choi et al., Vascul. Pharmacol. 2015 72:130-140).
Four HDAC inhibitors are currently approved for the treatment of some cancers. These are suberanilohydroxamic acid (Vorinostat; Zolinza®) for the treatment of cutaneous T cell lymphoma and multiple myeloma; Romidepsin (FK228; FR901228; Istodax®) for the treatment of peripheral T cell lymphoma; Panobinostat (LBH-589; Farydak®) for the treatment of multiple myeloma; and belinostat (PXD101; Beleodaq®) for the treatment of peripheral T cell lymphoma. However, these drugs are of limited effectiveness and can give rise to unwanted side effects. Thus there is a need for HDAC inhibitors with an improved safety-efficacy profile.